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Fox Proteins and Cancers: Old Proteins with Emerging New Tales

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 January 2019) | Viewed by 58320

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Prof. Dr. Eric W.F. Lam

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Division of Cancer, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
Interests: cancer; breast cancer; forkhead; fatty acids; transcription factor; drug resistance

Dr. Yannasittha Jiramongkol

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Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
Interests: cancer; breast cancer; forkhead; fatty acids; transcription factor; drug resistance

Dr. Shang Yao

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Special Issue Information

Dear Colleagues,

Forkhead box (Fox) proteins are an evolutionary conserved family of transcription regulators, related by the presence of a ‘forkhead’ or ‘winged-helix’ DNA-binding domain. In mammals, they are categorised into 19 subgroups (FoxA to FoxS) based on their sequence homology in and outside the ‘forkhead’ domain. The Fox proteins regulate the expression of a great diversity of genes involved in normal cell survival, proliferation, and differentiation, as well as cell longevity. Many of these Fox proteins are normally vital to the key developmental processes, and their dysregulation will have detrimental effects. Perhaps not surprisingly, deregulated Fox expression has been linked to cancer initiation, progression, and drug resistance. A comprehensive study of the mechanistic complexity that governs these transcription regulators will uncover important cancer diagnostic markers and therapeutic targets in the clinic. This Special Issue aims to bring together a collection of original research articles and incisive reviews that seek to discover and evaluate the links between Fox proteins and cancers, focusing predominantly on the well-studied FoxA, FoxC, FoxM, FoxO, and FoxP proteins.

Prof. Dr. Eric W.F. Lam
Dr. Yannasittha Jiramongkol
Dr. Shang Yao
Guest Editors

Manuscript Submission Information

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Published Papers (10 papers)

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Research

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24 pages, 6526 KiB

Open AccessArticle

EP300 and SIRT1/6 Co-Regulate Lapatinib Sensitivity Via Modulating FOXO3-Acetylation and Activity in Breast Cancer

by Zimam Mahmud, Ana R. Gomes, Hee Jin Lee, Sathid Aimjongjun, Yannasittha Jiramongkol, Shang Yao, Stefania Zona, Glowi Alasiri, Gyungyub Gong, Ernesto Yagüe and Eric W.-F. Lam

Cancers 2019, 11(8), 1067; https://doi.org/10.3390/cancers11081067 - 28 Jul 2019

Cited by 25 | Viewed by 5813

Abstract

Forkhead Box O3 (FOXO3) is a tumor suppressor whose activity is fine-tuned by post-translational modifications (PTMs). In this study, using the BT474 breast cancer cells and a recently established lapatinib resistant (BT474-Lap^R) cell line, we observed that higher FOXO3 and acetylated (Ac)-FOXO3 levels correlate with lapatinib sensitivity. Subsequent ectopic expression of EP300 led to an increase in acetylated-FOXO3 in sensitive but not in resistant cells. Drug sensitivity assays revealed that sensitive BT474 cells show increased lapatinib cytotoxicity upon over-expression of wild-type but not acetylation-deficient EP300. Moreover, FOXO3 recruitment to target gene promoters is associated with target gene expression and drug response in sensitive cells and the inability of FOXO3 to bind its target genes correlates with lapatinib-resistance in BT474-Lap^R cells. In addition, using SIRT1/6 specific siRNAs and chemical inhibitor, we also found that sirtuin 1 and -6 (SIRT1 and -6) play a part in fine-tuning FOXO3 acetylation and lapatinib sensitivity. Consistent with this, immunohistochemistry results from different breast cancer subtypes showed that high SIRT6/1 levels are associated with constitutive high FOXO3 expression which is related to FOXO3 deregulation/inactivation and poor prognosis in breast cancer patient samples. Collectively, our results suggest the involvement of FOXO3 acetylation in regulating lapatinib sensitivity of HER2-positive breast cancers. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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20 pages, 10356 KiB

Open AccessArticle

Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells

by Yujie Liu, Chunrong Bao, Liqing Wang, Rongxiang Han, Ulf H. Beier, Tatiana Akimova, Philip A. Cole, Sharon Y. R. Dent and Wayne W. Hancock

Cancers 2019, 11(4), 554; https://doi.org/10.3390/cancers11040554 - 18 Apr 2019

Cited by 9 | Viewed by 3917

Abstract

Functions of the GCN5-related N-acetyltransferase (GNAT) family of histone/protein acetyltransferases (HATs) in Foxp3+ T-regulatory (Treg) cells are unexplored, despite the general importance of these enzymes in cell biology. We now show that two prototypical GNAT family members, GCN5 (general control nonrepressed-protein 5, lysine acetyltransferase (KAT)2a) and p300/CBP-associated factor (p300/CBP-associated factor (PCAF), Kat2b) contribute to Treg functions through partially distinct and partially overlapping mechanisms. Deletion of Gcn5 or PCAF did not affect Treg development or suppressive function in vitro, but did affect inducible Treg (iTreg) development, and in vivo, abrogated Treg-dependent allograft survival. Contrasting effects were seen upon targeting of each HAT in all T cells; mice lacking GCN5 showed prolonged allograft survival, suggesting this HAT might be a target for epigenetic therapy in allograft recipients, whereas transplants in mice lacking PCAF underwent acute allograft rejection. PCAF deletion also enhanced anti-tumor immunity in immunocompetent mice. Dual deletion of GCN5 and PCAF led to decreased Treg stability and numbers in peripheral lymphoid tissues, and mice succumbed to severe autoimmunity by 3–4 weeks of life. These data indicate that HATs of the GNAT family have contributions to Treg function that cannot be replaced by the functions of previously characterized Treg HATs (CBP, p300, and Tip60), and may be useful targets in immuno-oncology. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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19 pages, 3936 KiB

Open AccessArticle

A Feedback Loop Formed by ATG7/Autophagy, FOXO3a/miR-145 and PD-L1 Regulates Stem-like Properties and Invasion in Human Bladder Cancer

by Junlan Zhu, Yang Li, Yisi Luo, Jiheng Xu, Huating Liufu, Zhongxian Tian, Chao Huang, Jingxia Li and Chuanshu Huang

Cancers 2019, 11(3), 349; https://doi.org/10.3390/cancers11030349 - 12 Mar 2019

Cited by 40 | Viewed by 3993 | Correction

Abstract

Programmed cell death protein 1 (PD-1) and its ligand PD-L1 blockade have been identified to target immune checkpoints to treat human cancers with durable clinical benefit. Several studies reveal that the response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells. However, the mechanistic pathways that regulate PD-L1 protein expression are not understood. Here, we reported that PD-L1 protein is regulated by ATG7-autophagy with an ATG7-initiated positive feedback loop in bladder cancer (BC). Mechanistic studies revealed that ATG7 overexpression elevates PD-L1 protein level mainly through promoting autophagy-mediated degradation of FOXO3a, thereby inhibiting its initiated miR-145 transcription. The lower expression of miR-145 increases pd-l1 mRNA stability due to the reduction of its direct binding to 3′-UTR of pd-l1 mRNA, in turn leading to increasing in pd-l1 mRNA stability and expression, and finally enhancing stem-like property and invasion of BC cells. Notably, overexpression of PD-L1 in ATG7 knockdown cells can reverse the defect of autophagy activation, FOXO3A degradation, and miR-145 transcription attenuation. Collectively, our results revealed a positive feedback loop to promoting PD-L1 expression in human BC cells. Our study uncovers a novel molecular mechanism for regulating pd-l1 mRNA stability and expression via ATG7/autophagy/FOXO3A/miR-145 axis and reveals the potential for using combination treatment with autophagy inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human BCs. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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22 pages, 2251 KiB

Open AccessEditor’s ChoiceArticle

Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer

by Carter J Barger, Connor Branick, Linda Chee and Adam R. Karpf

Cancers 2019, 11(2), 251; https://doi.org/10.3390/cancers11020251 - 21 Feb 2019

Cited by 118 | Viewed by 12923

Abstract

FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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14 pages, 2160 KiB

Open AccessArticle

Infiltration of FoxP3+ Regulatory T Cells is a Strong and Independent Prognostic Factor in Head and Neck Squamous Cell Carcinoma

by Imelda Seminerio, Géraldine Descamps, Sophie Dupont, Lisa de Marrez, Jean-Alexandre Laigle, Jérôme R Lechien, Nadège Kindt, Fabrice Journe and Sven Saussez

Cancers 2019, 11(2), 227; https://doi.org/10.3390/cancers11020227 - 15 Feb 2019

Cited by 64 | Viewed by 3468

Abstract

Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a large heterogeneity in terms of the location and risk factors. For a few years now, immunotherapy seems to be a promising approach in the treatment of these cancers, but a better understanding of the immune context could allow to offer a personalized treatment and thus probably increase the survival of HNSCC patients. In this context, we evaluated the infiltration of FoxP3+ Tregs on 205 human formalin-fixed paraffin-embedded HNSCC and we assessed its prognostic value compared to other potential prognostic factors, including HPV infection. First, we found a positive correlation of FoxP3+ Treg infiltration between the intra-tumoral (IT) and the stromal (ST) compartments of the tumors (p < 0.0001). A high infiltration of these cells in both compartments was associated with longer recurrence-free (ST, RFS, p = 0.007; IT, RFS, p = 0.019) and overall survivals (ST, OS, p = 0.002; ST, OS, p = 0.002) of HNSCC patients. Early tumor stage (OS, p = 0.002) and differentiated tumors (RFS, p = 0.022; OS, p = 0.043) were also associated with favorable prognoses. Multivariate analysis revealed that FoxP3+ Treg stromal infiltration, tumor stage and histological grade independently influenced patient prognosis. In conclusion, the combination of these three markers seem to be an interesting prognostic signature for HNSCC. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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Review

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19 pages, 1178 KiB

Open AccessReview

The Role of Forkhead Box Proteins in Acute Myeloid Leukemia

by Carmelo Gurnari, Giulia Falconi, Eleonora De Bellis, Maria Teresa Voso and Emiliano Fabiani

Cancers 2019, 11(6), 865; https://doi.org/10.3390/cancers11060865 - 21 Jun 2019

Cited by 19 | Viewed by 4007

Abstract

Forkhead box (FOX) proteins are a group of transcriptional factors implicated in different cellular functions such as differentiation, proliferation and senescence. A growing number of studies have focused on the relationship between FOX proteins and cancers, particularly hematological neoplasms such as acute myeloid leukemia (AML). FOX proteins are widely involved in AML biology, including leukemogenesis, relapse and drug sensitivity. Here we explore the role of FOX transcription factors in the major AML entities, according to “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia”, and in the context of the most recurrent gene mutations identified in this heterogeneous disease. Moreover, we report the new evidences about the role of FOX proteins in drug sensitivity, mechanisms of chemoresistance, and possible targeting for personalized therapies. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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19 pages, 2314 KiB

Open AccessReview

Chasing the FOXO3: Insights into Its New Mitochondrial Lair in Colorectal Cancer Landscape

by Valentina Grossi, Candida Fasano, Valentina Celestini, Martina Lepore Signorile, Paola Sanese and Cristiano Simone

Cancers 2019, 11(3), 414; https://doi.org/10.3390/cancers11030414 - 23 Mar 2019

Cited by 17 | Viewed by 4832

Abstract

Colorectal cancer (CRC) poses a formidable challenge in terms of molecular heterogeneity, as it involves a variety of cancer-related pathways and molecular changes unique to an individual’s tumor. On the other hand, recent advances in DNA sequencing technologies provide an unprecedented capacity to comprehensively identify the genetic alterations resulting in tumorigenesis, raising the hope that new therapeutic approaches based on molecularly targeted drugs may prevent the occurrence of chemoresistance. Regulation of the transcription factor FOXO3a in response to extracellular cues plays a fundamental role in cellular homeostasis, being part of the molecular machinery that drives cells towards survival or death. Indeed, FOXO3a is controlled by a range of external stimuli, which not only influence its transcriptional activity, but also affect its subcellular localization. These regulation mechanisms are mediated by cancer-related signaling pathways that eventually drive changes in FOXO3a post-translational modifications (e.g., phosphorylation). Recent results showed that FOXO3a is imported into the mitochondria in tumor cells and tissues subjected to metabolic stress and cancer therapeutics, where it induces expression of the mitochondrial genome to support mitochondrial metabolism and cell survival. The current review discusses the potential clinical relevance of multidrug therapies that drive cancer cell fate by regulating critical pathways converging on FOXO3a. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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20 pages, 1857 KiB

Open AccessReview

FOXK2 Transcription Factor and Its Emerging Roles in Cancer

by Gabriela Nestal de Moraes, Luciana da Torre Carneiro, Raquel Ciuvalschi Maia, Eric Wing-Fai Lam and Andrew David Sharrocks

Cancers 2019, 11(3), 393; https://doi.org/10.3390/cancers11030393 - 20 Mar 2019

Cited by 33 | Viewed by 5570

Abstract

Forkhead box (FOX) transcription factors compose a large family of regulators of key biological processes within a cell. FOXK2 is a member of FOX family, whose biological functions remain relatively unexplored, despite its description in the early nineties. More recently, growing evidence has been pointing towards a role of FOXK2 in cancer, which is likely to be context-dependent and tumour-specific. Here, we provide an overview of important aspects concerning the mechanisms of regulation of FOXK2 expression and function, as well as its complex interactions at the chromatin level, which orchestrate how it differentially regulates the expression of gene targets in pathophysiology. Particularly, we explore the emerging functions of FOXK2 as a regulator of a broad range of cancer features, such as cell proliferation and survival, DNA damage, metabolism, migration, invasion and metastasis. Finally, we discuss the prognostic value of assessing FOXK2 expression in cancer patients and how it can be potentially targeted for future anticancer interventions. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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18 pages, 1039 KiB

Open AccessReview

The Diverse Consequences of FOXC1 Deregulation in Cancer

by L. Niall Gilding and Tim C. P. Somervaille

Cancers 2019, 11(2), 184; https://doi.org/10.3390/cancers11020184 - 05 Feb 2019

Cited by 34 | Viewed by 5671

Abstract

Forkhead box C1 (FOXC1) is a transcription factor with essential roles in mesenchymal lineage specification and organ development during normal embryogenesis. In keeping with these developmental properties, mutations that impair the activity of FOXC1 result in the heritable Axenfeld-Rieger Syndrome and other congenital disorders. Crucially, gain of FOXC1 function is emerging as a recurrent feature of malignancy; FOXC1 overexpression is now documented in more than 16 cancer types, often in association with an unfavorable prognosis. This review explores current evidence for FOXC1 deregulation in cancer and the putative mechanisms by which FOXC1 confers its oncogenic effects. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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16 pages, 1177 KiB

Open AccessReview

Role of FoxO Proteins in Cellular Response to Antitumor Agents

by Giovanni Luca Beretta, Cristina Corno, Nadia Zaffaroni and Paola Perego

Cancers 2019, 11(1), 90; https://doi.org/10.3390/cancers11010090 - 14 Jan 2019

Cited by 57 | Viewed by 7286

Abstract

FoxO proteins (FoxOs) are transcription factors with a common DNA binding domain that confers selectivity for DNA interaction. In human cells, four proteins (FoxO1, FoxO3, FoxO4 and FoxO6), with redundant activity, exhibit mainly a positive effect on genes involved in cell cycle, apoptosis regulation and drug resistance. Thus, FoxOs can affect cell response to antitumor agent treatment. Their transcriptional activity depends on post-translational modifications, including phosphorylation, acetylation, and mono/poly-ubiquitination. Additionally, alterations in microRNA network impact on FoxO transcripts and in turn on FoxO levels. Reduced expression of FoxO1 has been associated with resistance to conventional agents (e.g., cisplatin) and with reduced efficacy of drug combinations in ovarian carcinoma cells. FoxO3 has been shown as a mediator of cisplatin toxicity in colorectal cancer. A requirement for FoxO3-induced apoptosis has been reported in cells exposed to targeted agents (e.g., gefitinib). Recently, the possibility to interfere with FoxO1 localization has been proposed as a valuable approach to improve cell sensitivity to cisplatin, because nuclear retention of FoxO1 may favor the induction of pro-apoptotic genes. This review focuses on the role of FoxOs in drug treatment response in tumor cells and discusses the impact of the expression of these transcription factors on drug resistance/sensitivity. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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